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"titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Efectos anticancerígenos de las heparinas" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">65 years ago, it was questioned whether heparin had non-antithrombotic effects, such as an effect on the placenta or anticancer effects, and if this possible effect could be used in cancer patients to improve their overall survival.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–7</span></a> But the truth is that although various studies have been carried out in the last 20 years,<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6–16</span></a> we do not know exactly how they work, and the clinical results are currently inconclusive in terms of their use as an adjunct treatment in cancer patients.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Therefore, in recent years, research has focused on the use of new technologies to use the part of the low molecular weight heparin (LMWH) in a more targeted and personalised way, such as the development of nanoparticles through the structural modification of the LMWH.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">It has already been shown that patients with malignant neoplasms treated with LMWH, together with cancer treatment, survive longer, not only because they avoid thromboembolic phenomena, but also because of a possible anti-tumour effect independent of its anticoagulant effect, probably antiangiogenic, in addition to others already described. These results have been corroborated in subsequent meta-analyses, where not only the effect on mortality favoured the LMWHs (<span class="elsevierStyleItalic">odds ratio</span> [OR]: 0.71), but in addition, the risk of serious bleeding complications was lower with LMWHs (OR: 0.57), although this did not reach statistical significance compared to unfractionated heparin.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> This meta-analysis also concludes that LMWHs are equivalent in preventing the recurrence of thrombotic events. In the multivariate analysis of the study, heparin proved to be an independent prognostic factor. In this case, patients with thrombosis and those treated with heparin survived longer with any of the prescribed regimens, in comparison to those who did not suffer from thrombosis, which in itself is associated with a worse prognosis, due to the comorbidity involved in a thrombotic phenomenon.</p><p id="par0020" class="elsevierStylePara elsevierViewall">But what has really aroused scientific curiosity is to understand the possible mechanisms of the anti-tumoral action of heparins. In the last 20 years these mechanisms of action have been studied and there are “proofs of concept” that show that they do exist.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,18</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">It is believed that the anti-tumour effect of heparins is due largely to their belonging to the family of glycosaminoglycans (GAGs), which are distributed in the extracellular matrix and regulate cell growth, which could be carried out by different mechanisms. These mechanisms include the antiangiogenic effect either by blocking the heparanase enzymes, blocking the tissular factor or inhibiting the thrombin.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Thrombin inhibition would impair cell growth in both clotting-dependent and -non-dependent manners.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Fibrin would also play an important role, since the coagulation system and fibrinolysis are involved in healing as a regulator of the angiogenesis and the situations of hypoxia, inflammation and tissue damage release angiogenic factors. In tumour tissues the coagulation/fibrinolysis system is unbalanced, with an increased fibrin production and inhibition of the fibrinolysis system. This does not only give rise to thrombosis, but it can also stimulate angiogenesis; supporting the development of tumour cells. The generation of thrombin would lead to depositing fibrin around tumour cells thereby preventing cell adhesion and angiogenesis.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Other mechanisms of action include: the inhibition of platelet adhesion and the inhibition of extracellular matrix formation (by blocking the heparanase action, which would prevent the extracellular matrix from degradation and the release of cytokines into the tumour microenvironment); the inhibition of the metastatic phenomenon (via the blockade of the action of the P-selectin and L-selectin adhesion molecules contributing to metastases); and some <span class="elsevierStyleItalic">in vitro</span> studies even suggest that heparins play a role as chemosensitisers.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">It can be concluded that some LMWH have been shown to have antiangiogenic effects <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>. In human leukaemia, lung cancer, and breast cancer cells, bemiparin has been shown to inhibit the formation of new capillaries and endothelial migration, induced by VEGF and fibroblast growth factor 2 (FGF-2).<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In addition, bemiparin, but not unfractionated heparin (UFH), showed an antiangiogenic and antivasculogenic effect in cell cultures of the umbilical vein endothelial cells and the endothelial progenitor cells, so it is important to choose the drug and its appropriate doses. Other LMWHs such as enoxaparin and tinzaparin, which are widely used in our environment, have also demonstrated these effects, such as heparanase inhibition or endothelial protection, respectively.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">But how many studies have been conducted so far and what is the evidence? Since 1992 several studies have been carried out. There have been at least 8 studies<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9–16</span></a> with different heparins, such as unfractionated heparin or LMWH such as bemiparin, tinzaparin, dalteparin or enoxaparin. Five described positive results in terms of overall survival, but 3 did not find this improvement. It must be said that these studies included resected non-small cell lung carcinomas, and pancreatic carcinomas, with or without thrombosis, and in different stages, hence the great variability of results. The Lebeau et al. studies<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> with calcium heparin in 1994, the ABEL study<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> with bemiparin in 2013, the FAMOUS study<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> with dalteparin in 2004, all found differences in overall survival, but no improvements were observed in the RASTEN study<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> with enoxaparin in 2017, the NIVALT-8 study with nadroparin in 2016,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> or the TILT study with tinzaparin in 2017.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The results of the meta-analysis are contradictory because the included studies are heterogeneous with aggressive tumours in different stages, and with different prognoses, treatments, etc. Therefore, the results have not been conclusive, and in the majority of cases the recommendations are to study the biomarkers to practise a more personalised medicine, and to conduct studies with more homogeneous populations. What these results have shown is a low level of evidence, and not a demonstration of improvement in survival with the use of LMWH as an adjunctive treatment.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">However, studies are currently being conducted on the tumour vascular normalisation hypothesis that has impacted in the field of new drug development and whose mechanism of action is antiangiogenic, like the LMWHs. The hypothesis posits that rather than destroying tumour vessels, the antiangiogenic drugs restore tumour veins and normalize the structure and function of the tumour vasculature, improving oxygenation and sensitivity to drug release. Hence the research has focused on the anti-angiogenic mechanisms of heparin. Some studies have shown that the dissolution of microthrombi and other proteins in the tumour microenvironment reduces interstitial pressure and this can improve the penetration of anti-tumour drugs. Preclinical phase studies have shown that LMWH is a potent inhibitor of VEGF, and it can temporarily normalise vasculature during antiangiogenic therapy.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Nowadays, nanopharmaceuticals have already been designed using this characteristic of LMWH with a potent normalisation of the vasculature, achieving good results in the modulation of the tumour microenvironment and enabling the anti-tumour drug to reach the tumour tissue and even improving the sensitivity of the tumour cells in immunotherapy. These findings are the theoretical basis for future combined anticancer therapies, as well as synergistic effects with other immunotherapies.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion, <span class="elsevierStyleItalic">in vitro</span> evidence exists of the anti-cancer effect of LMWH, but the studies carried out are heterogeneous and with contradictory results, so no improvement in survival rates have been seen that support the use of LMWH as an adjunctive treatment. But it seems that progress is being made in other directions, looking for new formulations or forms of administration, such as nanoparticles, that would have anticancer effects and that open a future to heparin, in the fight against cancer.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Santamaría A, Suito M. Efectos anticancerígenos de las heparinas. Med Clin (Barc). 2020;154:398–399.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heparins and cancer survival: where do we stand?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S. Noble" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Thromb Res" "fecha" => "2014" "volumen" => "133 Suppl" "paginaInicial" => "S133" "paginaFinal" => "8" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The role of the hemostatic system in tumor growth, metastasis, and angiogenesis: tissue factor is a bifunctional molecule capable of inducing both fibrin deposition and angiogenesis in cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F.R. Rickles" 1 => "M. Shoji" 2 => "K. Abe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/BF02981930" "Revista" => array:6 [ "tituloSerie" => "Int J Hematol" "fecha" => "2001" "volumen" => "73" "paginaInicial" => "145" "paginaFinal" => "150" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11372724" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tissue factor and angiogenesis in cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P.M. Fernández" 1 => "F.R. Rickles" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/00062752-200209000-00003" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Hematol" "fecha" => "2002" "volumen" => "9" "paginaInicial" => "401" "paginaFinal" => "406" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12172458" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tissue factor, thrombin, and cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F.R. Rickles" 1 => "S. Patierno" 2 => "P.M. Fernández" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Chest" "fecha" => "2003" "volumen" => "124 Suppl3" "paginaInicial" => "S58" "paginaFinal" => "68" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Two cases of neoplasms not justified for classical therapy, treated with intravenous injections of heparin and intramuscular injections of leech extracts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Albert-Weil" 1 => "J. Nehorias" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Rev Pathol Gen Physiol Clin" "fecha" => "1954" "volumen" => "54" "paginaInicial" => "1014" "paginaFinal" => "1020" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/13204989" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of low- molecular-weight heparin on survival in patients with advanced malignancy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.P.W. Klerk" 1 => "S.M. Smorenburg" 2 => "H.-M. Otten" 3 => "A.W.A. Lensing" 4 => "M.H. Prins" 5 => "F. Piovella" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2005.03.134" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2005" "volumen" => "23" "paginaInicial" => "2130" "paginaFinal" => "2135" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15699479" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enoxaparin attenuates mouse colon cancer liver metastases by inhibiting heparanase and interferon-γ-inducible chemokines" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Diaafar" 1 => "I. Dunnan-Sautier" 2 => "Gonelle-Gispert" 3 => "S. Lacotte" 4 => "A. de Agostini" 5 => "M. Petro" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Anticancer Res" "fecha" => "2016" "volumen" => "36" "paginaInicial" => "4019" "paginaFinal" => "4032" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27466508" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Endothelial barrier protective properties of low molecular weight heparin: a novel potential tool in the prevention of cancer metastasis?" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Kevane" 1 => "K. Egan" 2 => "S. Allen" 3 => "P. Maguire" 4 => "E. Neary" 5 => "Á Lennon" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Res Pract Thromb Haemost" "fecha" => "2017" "volumen" => "20" "paginaInicial" => "23" "paginaFinal" => "32" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Lower mortality in cancer patients treated with low-molecular-weight versus standard heparin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D. Green" 1 => "R.D. Hull" 2 => "R. Brant" 3 => "G.F. Pineo" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0140-6736(92)92065-n" "Revista" => array:5 [ "tituloSerie" => "Lancet" "fecha" => "1992" "volumen" => "339" "paginaInicial" => "1476" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1351143" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "LMWH bemiparin and ULMWH RO-14 reduce the endotelial angiogenic features elicited by leukemia, lung cancer or breast cancer cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Vignoli" 1 => "M. Marchetti" 2 => "L. Russo" 3 => "E. Cantalino" 4 => "E. Diani" 5 => "G. Bonacina" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/07357907.2010.543217" "Revista" => array:6 [ "tituloSerie" => "Cancer Invest" "fecha" => "2011" "volumen" => "29" "paginaInicial" => "153" "paginaFinal" => "161" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21261475" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Subcutaneous heparin treatment increases survival in small cell lung cancer. Petites Cellules Group" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Lebeau" 1 => "C. Chastang" 2 => "J.M. Brechot" 3 => "F. Capron" 4 => "B. Dautzenberg" 5 => "C. Delaisements" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/1097-0142(19940701)74:1<38::aid-cncr2820740108>3.0.co;2-e" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "1994" "volumen" => "74" "paginaInicial" => "38" "paginaFinal" => "45" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8004580" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R. Lecumberri" 1 => "G. López Vivanco" 2 => "A. Font" 3 => "E. González Billalabeitia" 4 => "A. Gurpide" 5 => "J. Gómez Codina" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.thromres.2013.09.026" "Revista" => array:6 [ "tituloSerie" => "Thromb Res" "fecha" => "2013" "volumen" => "132" "paginaInicial" => "666" "paginaFinal" => "670" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24491267" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS)" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.K. Kakkar" 1 => "M.N. Levine" 2 => "Z. Kadziola" 3 => "N.R. Lemoine" 4 => "V. Low" 5 => "H.K. Patel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2004.10.002" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2004" "volumen" => "22" "paginaInicial" => "1944" "paginaFinal" => "1948" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15143088" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Swedish Lung Cancer Study Group (SLUSG). Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small cell lung cancer: the RASTEN trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Ek" 1 => "E. Gezelius" 2 => "B. Bergman" 3 => "P.O. Bendahl" 4 => "H. Anderson" 5 => "J. Sundberg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdx716" "Revista" => array:6 [ "tituloSerie" => "Ann Oncol" "fecha" => "2018" "volumen" => "29" "paginaInicial" => "398" "paginaFinal" => "404" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29106448" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "NVALT Study Group, the Netherlands. Randomised phase · study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H.J.M. Groen" 1 => "E.H.F.M. van der Heijden" 2 => "T.J. Klinkenberg" 3 => "B. Biesma" 4 => "J. Aerts" 5 => "A. Verhagen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/s41416-019-0533-3" "Revista" => array:6 [ "tituloSerie" => "Br J Cancer" "fecha" => "2019" "volumen" => "121" "paginaInicial" => "372" "paginaFinal" => "377" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31337877" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of low-molecular-weight heparin on survival of patient with resected non-small cell lung cancer: the tinzaparin in tumor lung trials (TILT) randomized Phase III. OC 46.5 ISTH" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Meyer" 1 => "B. Besse" 2 => "H. Doubre" 3 => "A. Charles-Nelson" 4 => "S. Aquilanti" 5 => "A. Izadifar" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:2 [ "titulo" => "XXVI ISTH Congress and 63rd Annual SCC Meeting" "serieFecha" => "2017" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "LMWH and its derivatives represent new rational for cancer therapy: construction strategies and combination therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Du" 1 => "Y. Yu" 2 => "C. Xu" 3 => "H. Xiong" 4 => "S. Yang" 5 => "J. Yao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.drudis.2019.06.011" "Revista" => array:6 [ "tituloSerie" => "Drug Discov Today" "fecha" => "2019" "volumen" => "24" "paginaInicial" => "2096" "paginaFinal" => "2104" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31228613" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.K. Gould" 1 => "A.D. Dembitzer" 2 => "R.L. Doyle" 3 => "T.J. Hastie" 4 => "A.M. Garber" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7326/0003-4819-130-10-199905180-00003" "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "1999" "volumen" => "130" "paginaInicial" => "800" "paginaFinal" => "809" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10366369" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000015400000010/v1_202005290855/S2387020620301145/v1_202005290855/en/main.assets" "Apartado" => array:4 [ "identificador" => "46797" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Editorial article" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000015400000010/v1_202005290855/S2387020620301145/v1_202005290855/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020620301145?idApp=UINPBA00004N" ]
